7V04

The N-terminal domain of PA endonuclease from the influenza H1N1 viral polymerase in complex with 6-bromo-3-hydroxy-4-oxo-1,4-dihydropyridine-2-carboxamide

Summary for 7V04

• Entry DOI: 10.2210/pdb7v04/pdb
• Descriptor: Polymerase acidic protein, MANGANESE (II) ION, 6-bromo-3-hydroxy-4-oxo-1,4-dihydropyridine-2-carboxamide, ... (4 entities in total)
• Functional Keywords: drug discovery, metal-binding pharmacophore, isosteres, influenza endonuclease, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Influenza A virus (A/California/04/2009(H1N1))
• Total number of polymer chains: 1
• Total formula weight: 22677.32

Authors

Kohlbrand, A.J.,Stokes, R.W.,Karges, J.,Seo, H.,Sankaran, B.,Cohen, S.M. (deposition date: 2022-05-09, release date: 2022-12-21, Last modification date: 2023-10-25)

Primary citation

Stokes, R.W.,Kohlbrand, A.J.,Seo, H.,Sankaran, B.,Karges, J.,Cohen, S.M.
Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors.
Acs Med.Chem.Lett., 14:75-82, 2023

PubMed Abstract: Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PA) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PA using a FRET-based enzymatic assay, and their mode of binding in PA was determined using X-ray crystallography.

PubMed: 36655124
DOI: 10.1021/acsmedchemlett.2c00434

Experimental method

X-RAY DIFFRACTION (1.91 Å)